Nature communications · 2025
Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules.
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Su Hang, Chen Li, Wu Jun, Cheng Zhongyi, Li Jing, Ren Yijiu, Xu Junfang, Dang Yifang, Zheng Mengge, Cao Yajuan, Gao Jiani, Dai Chenyang, Hu Xuefei, Xie Huikang, Chen Jianxia, Luo Tao, Zhu Jun, Wu Chunyan, Sha Wei, Chen Chang, Liu Haipeng
Аннотация
Lung adenocarcinoma (LUAD) radiologically displayed as subsolid nodules (SSNs) is prevalent. Nevertheless, the precise clinical management of SSNs necessitates a profound understanding of their tumorigenesis and progression. Here, we analyze 66 LUAD displayed as SSNs covering 3 histological stages including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) by incorporating genomics, proteomics, phosphoproteomics and glycoproteomics. Intriguingly, cholesterol metabolism is aberrantly regulated in the preneoplastic AIS stage. Importantly, target ablation of proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the initiation of LUAD. Furthermore, sustained endoplasmic reticulum stress is demonstrated to be a hallmark and a reliable biomarker of AIS progression to IAC. Consistently, target promotion of ER stress profoundly retards LUAD progression. Our study provides comprehensive proteogenomic landscape of SSNs, sheds lights on the tumorigenesis and progression of SSNs and suggests preventive and therapeutic strategies for LUAD.